Dose–Response Effect of Glucagon on Glucose, Beta-Cell Secretion and Metabolism in Healthy Individuals

Abstract

Aim: Glucagon is a key regulator of glucose and energy metabolism, yet the dose–response effects of glucagon on markers of metabolism in humans are not fully characterised. We investigated the dose-dependent effects of glucagon on glucose metabolism, β-cell secretion and markers of hepatic metabolism in healthy adults. Materials and Methods: Fifteen healthy, lean adults underwent a 180-min stepwise intravenous infusion of native human glucagon at six increasing doses (0.01, 0.1, 0.5, 1, 10 and 50 ng × kg−1 × min−1). Plasma glucose, insulin, C-peptide, cyclic AMP (cAMP), non-esterified fatty acids, triglycerides, total amino acids and urea were measured repeatedly throughout the study. Results: Plasma glucose increased in a dose-dependent manner, with significant stepwise elevations observed from intermediate infusion rates and reaching peak levels at supraphysiological glucagon levels. Insulin and C-peptide levels rose markedly, reflecting β-cell activation. Plasma cAMP increased only during the highest glucagon infusion rate, despite earlier metabolic responses. Plasma non-esterified fatty acids, triglycerides and total amino acids declined at higher glucagon doses, whilst plasma urea decreased gradually from the second infusion rate onward. Conclusion: Infusion of glucagon results in dose-dependent metabolic effects in healthy humans. The differential timing of glucose, lipid and amino acid responses relative to systemic cAMP elevations could be consistent with pathway-specific activation thresholds rather than uniform signalling. These findings provide new insights into human glucagon physiology with potential relevance for metabolic diseases.